Invasion of a pathogen (bacterium, virus, parasite or the like) into a host (human body or animal body) or generation of an endogenous inflammatory substance causes inflammatory reactions in which, for example, temporary contraction of arteriolae occurs at the site of invasion of the pathogen or the site of generation of the inflammatory substance, and expansion and hyperemia then occur, leading to local slowness of blood flow at the site of invasion of the pathogen or the site of generation of the inflammatory substance.
This causes adhesion of leukocytes to the vascular wall, and chemical mediators released from various immunocytes then act on the leukocytes to cause them to pass through the vascular wall by amoeboid movement and to allow their migration. Known examples of the chemical mediators include histamine, serotonin and lymphokines. Mast cells, which produce and release histamine and serotonin, are a type of lymphocytes that play a central role in the inflammatory reaction. Similarly to mast cells, macrophages also produce and release chemical mediators such as TNF.
The leukocytes whose migration was induced by the inflammatory reaction are attracted by the pathogen or the like, and this causes elimination (clearance) of the pathogen from the body by humoral immunity accompanied by antigen-antibody reaction and by cell-mediated immunity in which cytotoxic T cells and the like are involved, resulting in prevention of the spread of infection. Thus, the inflammatory reaction, and immune reactions that occur based on the inflammatory reaction, are extremely important for maintaining homeostasis of a living body.
On the other hand, the inflammatory reaction causes not only the biological defense described above, but also adverse signs/symptoms such as flare, fever, swelling, pain and dysfunction. Specific examples of such symptoms include allergic diseases, and various types of acute and chronic inflammations. Also in autoimmune diseases, in which the absence of immunological tolerance causes an autoimmune response, tissue injury occurs due to the inflammatory reaction.
That is, for prevention of a disease accompanied by the inflammatory reaction, it is important to kill the pathogen that causes the inflammatory reaction using antibiotics (antimicrobial agents), or to administer an agent that increases the immune function in the living body (immunostimulant) to eliminate the pathogen before an excessive inflammatory reaction occurs.
On the other hand, known examples of methods for amelioration or treatment of a disease accompanied by the inflammatory reaction include suppression of inflammation by administration of an agent (anti-inflammatory agent (immunosuppressant)) that decreases excessively activated immune function by, for example, suppression of release of chemical mediators.
For example, Patent Document 1 discloses, as an immunostimulant, an activating agent for the function of dendritic cells, which are antigen-presenting cells responsible for activation of various immunocytes. More specifically, the agent comprises as an effective component(s) at least one branched chain amino acid selected from isoleucine, leucine and valine.
Patent Document 2 discloses, as an anti-inflammatory agent (immunosuppressant), an agent comprising the SPARC (Secreted protein which is acidic and rich in cystein) peptide and a pharmaceutical carrier.
The following autoimmune diseases, allergic diseases and the like are known.
Celiac disease, or coeliac disease, is an autoimmune disease and is a progressive enteritis that is triggered by an immune reaction to gluten, which is a protein contained in wheat, barley, rye and the like. The incidence of this disease in the United Kingdom, Europe and the United States is one or more per 300 individuals.
Gluten, which is a mixture of two proteins gliadin and glutenin, is found in wheat, barley and rye. Gluten reacts with the small intestine and activates an immune system that attacks the fine small-intestinal epithelium, which is necessary for absorption of nutrients and vitamins, to cause injury.
When a patient with celiac disease takes a food or the like containing gluten, a gliadin-derived peptide, which cannot be digested by digestive enzymes of human and is contained in wheat as a fraction of a plant protein gluten, is deaminated by TG2 in the duodenal submucosal tissue to produce an antigen, which then causes production of autoantibodies.
Celiac disease occurs in genetically sensitive individuals having any of: HLA-DQ2 (which is retained in about 90% of individuals), which is encoded by HLA-DQA1 and HLA-DQB1; HLA-DQ2 mutants; and HLA-DQ8.
Such individuals show induction of an immune response to peptides induced from water-insoluble proteins in flour, gluten, and related proteins in rye and barley, which immune response is limited to inappropriate HLA-DQ2 and/or DQ8 and mediated by CD4+ T cells.
This immune reaction triggers an attack of the autoimmune system on the small-intestinal epithelial tissue to cause inflammation and then injury of villi and the like, leading to destruction of the epithelial cells themselves. As a result, nutrients cannot be absorbed from the small intestine, and the patient suffers from malnutrition irrespective of the dietary intake and the like.
Ulcerative colitis, which is a representative inflammatory bowel disease (IBD), is a collective term for chronic diseases that cause inflammation of unknown origin mainly in the digestive tract, and is a chronic disease in which inflammation occurs in the large intestine to form ulcers.
Inflammatory bowel disease (IBD) is a collective term used for describing two gastrointestinal disorders (Crohn's disease (CD) and ulcerative colitis (UC)) whose causes are unknown.
In Crohn's disease, a larger area is affected compared to ulcerative colitis, and inflammation and ulcers are found in almost the whole area of the digestive tract. Inflammatory bowel disease (IBD) occurs worldwide, and as many as two million people are reported to have suffered from Crohn's disease. The progression and prognosis of IBD widely vary.
In inflammatory bowel disease (IBD), diarrhea and bloody stool continue for a long period while the severity of symptoms changes with time. The cause of the disease has not been elucidated, and, in a major hypothesis, the continuous enteritis is thought to be caused by immune reactions to foods and enterobacteria due to disorder of immunological tolerance in the intestinal tract.
At present, there is no fundamental therapeutic method for the disease, and examples of therapies for inflammatory bowel disease include dietetic treatment; and use of an antidiarrheal (e.g., anticholinergic, loperamide or diphenoxylate), anti-inflammatory agent (e.g., steroid drug such as aminosalicylic acid, sulfasalazine, mesalamine, olsalazine, balsalazide or prednisolone; or aminosalicylic acid) or immunosuppressant (e.g., azathioprine, mercaptopurine or cyclosporin).
Surgical operations are required over a period of 10 years in 10% to 15% of the patients with IBD, and they have higher risk of occurrence of intestinal cancer.
In Crohn's disease, bacteria are involved in the onset and the progression of the disease, and intestinal inflammation in Crohn's disease is well-known for its frequent responsiveness to antibiotics and susceptibility to bacterial fecal flow. Common intestinal microorganisms and novel pathogens have been suggested to have associations with Crohn's disease, based on direct detection or anti-microbial immune responses associated with the disease.
Moreover, in a number of genetically susceptible models of chronic colitis, luminal microorganisms are indispensable cofactors for the disease, and animals kept in a microbe-free environment do not develop colitis.
The combination of genetic factors, exogenous causes and the endogenous microbiota may contribute to the immune-mediated injury of the intestinal mucosa found in inflammatory bowel disease.
It is also known that development of ulcerative colitis is associated with polymorphisms in 3 gene regions, that is, the FCGR2A gene, which encodes a receptor protein present on the surface of immunocytes; s8LC26A3, which encodes a transporter of chlorine ions and hydrogen carbonate ions; and a gene in the 13q12 region whose function is unknown (Non-patent Document 3).
However, in spite of abundant direct and indirect evidence on the role of intestinal microorganisms in Crohn's disease, no pathogenic organism or antigen has been identified to contribute to the impaired immunoregulation found in this disease. Tools useful for elucidation of the pathologies of the inflammatory bowel diseases (Crohn's disease and inflammatory enteritis), and medicaments for treatment and the like of these diseases have been demanded.
Atopic dermatitis is caused by entrance of an allergic substance (antigen) into the body followed by production of periostin due to stimulation by substances (interleukins 4 and 13) secreted from activated immunocytes, and then binding of the periostin to another protein “integrin” on the surface of keratinocytes in the skin, to cause inflammation.
The binding of periostin to integrin causes production of other inflammation-inducing substances, and the symptoms continue even in the absence of the antigen, resulting in chronicity. It has been shown, by an experiment using mice, that inhibition of binding of periostin to integrin using an inhibitor prevents occurrence of atopic dermatitis (Non-patent Document 4).
Although the major cause of atopic dermatitis has become evident, further elucidation of the pathology of atopic dermatitis, analysis of association of atopic dermatitis with other inflammatory diseases, and medicaments for atopic dermatitis that can be used in combination with the above inhibitor, are demanded.
Bronchial asthma is a respiratory disease in which bronchial inflammation triggered by an allergic reaction or infection with a bacterium or virus becomes chronic to thereby cause increased airway hyperresponsiveness and reversible airway narrowing, leading to symptoms such as attacks of wheezing, and cough. Further, bronchial asthma is said to be caused by the combination of airway hyperresponsiveness, allergic diathesis and environment. Recurrent symptoms such as wheezing, apnea, chest tightness and cough occur especially at night or in the early morning.
A number of cells and cellular components, especially mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells play roles in inflammation of the airway. Inflammation is associated with plasma exudation, edema, smooth muscle enlargement, mucus plugging, and epithelial changes. Further, inflammation causes associated increases in bronchial hyperresponsiveness to various stimuli.
Inflammation of the airway induces atrophy of airway smooth muscle, microvascular rupture and bronchial hyperresponsiveness. As the responsiveness of the airway increases, the symptoms become more severe and continuous, and daily variation of the pulmonary function increases. The mechanism of involvement of airway inflammation in the bronchial responsiveness is unknown, and tools useful for elucidation of the pathology of asthma, and medicaments and the like have been demanded.
It is known that a group of receptor molecules called MAIR (Myeloid Associated Ig like Receptors) are expressed on the cell membrane of myeloid (bone marrow) cells responsible for natural immunity (Non-patent Document 1). Among these, MAIR-I, which is also known as CD300a (also referred to as “LMIR1” or “CLM-8”), is expressed in macrophages, mast cells, granulocytes (neutrophils) and dendritic cells, and known to be an inhibitory receptor that associates with phosphatase via the ITIM (Immunoreceptor tyrosine-based inhibitory motif) sequence in the intracellular domain to transmit an inhibitory signal (Non-patent Document 2). However, the ligand for this receptor is unknown, and the receptor has been the so-called orphan receptor.